Defective natural killer–cell cytotoxic activity in NFKB2-mutated CVID-like disease

  • Zoller Ee
  • Lykens J
  • Terrell C
  • et al.
Citations of this article
Mendeley users who have this article in their library.
Get full text


Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by low immunoglobulin serum levels, low vaccine responses, and recurrent infections. The clinical presentation of CVID comprises a variable mixture of recurrent infections, autoimmune phenomena, granulomatous disease, and lymphoproliferation. The underlying genetic mechanisms have been elucidated in the last few years in less than 10% to 15% of the cases and involve mutations in CD19, MS4A1 (CD20), CR2 (CD21), ICOS, TNFRSF13C, TNFRSF13B, PLCG2 (phospholipase Cg2), CD81, LRBA, and PRKCD (protein kinase Cd). 1-3 Recently, germline heterozygous mutations in NFKB2 were identified in 10 patients to be associated with early-onset CVID with autoimmunity in most cases, 4,5 profound B-cell deficiency, 6 or a CVID-like phenotype. 7 All affected patients had hypogamma-globulinemia with variable association of the following clinical and immunologic features: central adrenal insufficiency (ACTH insufficiency), alopecia totalis or areata, trachyonychia, variable natural killer (NK) cell numbers, and defects in peripheral T and B cells. We report on a male patient with early-onset CVID who carried the heteroyzgous p.Arg853* mutation in NFKB2 and later developed central adrenal insufficiency (ACTH insufficiency), alopecia totalis, and trachyonychia. An extensive immunologic work-up was performed that, besides confirming the presence of T-and B-cell defects, revealed, as a novel finding, impaired NK-cell cytotoxic activity in vitro, despite normal NK cell counts. The index patient was born to Italian nonrelated parents. Routine laboratory investigation was performed at age 15 months for growth delay and showed profound hypogammaglobulinemia —IgG, 95 mg/dL (normal values for age, 264-1509 mg/dL); IgA, less than 5 mg/dL (normal values for age, 17-178 mg/dL); IgM, less than 5 mg/dL (normal values for age, 48-337 mg/dL)—in the presence of normal peripheral B-cell counts (CD19 1 , 16.5%). Immunoglobulin replacement treatment was initiated. During follow-up, the patient presented with occasional infections of the upper respiratory tract. He developed alopecia totalis at the age of 4 years, followed by the development of trachyonychia. Endocrinological evaluation following a hypoglycemic episode (blood glycemic level, 26 mg/dL) revealed ACTH and cortisol insufficiency for which he was placed on replacement treatment with hydrocortisone. During adolescence, he developed hypothyroidism and required hormone replacement therapy. On the identification of hypogammaglobulinemia, a more extensive immunologic work-up revealed abnormalities of both T and B cells, namely, an accumulation of T cells in the early stages of differentiation with reduction of the terminal stages of T-cell development, for both CD4 and CD8 subsets, and the typical peripheral B-cell block of CVID with reduction in memory B cells, both switched and IgM memory ones, and lack of plasma cells (Table I). Proliferative responses to mitogens were normal (Table I). On the description of NFKB2 mutations associated with early-onset CVID, ACTH insufficiency, alopecia totalis, and trachyonichia, 4,5 direct gene sequencing for NFKB2 was performed for the index patient. A c.2557C>T substitution was found, leading to the non-sense mutation p.Arg853* (Fig 1). This is a de novo mutation because the patient's parents were wild type for this mutation. Interestingly, all patients described so far to be mutated in NFKB2, with the exception of 3 family members carrying a missense mutation, 6 carry de novo mutations. 4,5,7 The p.Arg853* mutation is disease-causing and was identified in the first description of NFKB2 mutations in CVID. 4 The index patient here described is the 11th patient to be affected with this genetic defect and the second one to carry the p.Arg853* mutation. Interestingly, the index patient is the first patient with germline NFKB2 mutation to develop clinically relevant hypothyroidism, underlying the clinical heterogeneity of this disorder. By reviewing the clinical data of the reported patients, 4-7 it is evident that some clinical features are common to all patients, whereas others are sporadic (see Table E1 in this article's Online Repository at Furthermore, the clinical and immunologic phenotype appears more severe in the presence of non-sense 4,5,7 rather than missense 6 mutations in NFKB2. Mutations in nuclear factor kappa B (NF-kB) essential




Zoller Ee, Lykens, J., Terrell, C., Aliberti, J., Filipovich, A., Henson, & Pm. (2015). Defective natural killer–cell cytotoxic activity in NFKB2-mutated CVID-like disease. Journal of Allergy and Clinical Immunology, 135(6), 1641–1643.

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free